Polymorphism of the MTHFR Gene is Associated with Altered Gene Expression in Colorectal Cancer

Aims: Folate supplementation appears to reduce colorectal cancer (CRC) risk. CRC risk is also modulated by the C to T polymorphism at position 677 of the methylenetetrahydrofolate reductase (MTHFR) gene which results in a thermolabile variant of MTHFR and is associated with reduced cellular folate levels. We looked for a relationship between MTHFR expression in colorectal tumour tissue and the C677T polymorphism. Methods: Thirty-nine patients with colorectal cancer who gave consent were studied. DNA was extracted from citrated blood and tumour tissue and genotyped for the MTHFR C677T polymorphism. Expression of MTHFR in colorectal tumour tissue and normal colonic mucosa from the same patient was quantified by 'real-time' PCR. Hypothesis testing was performed on ranks of the ratio of MTHFR expression to 18S. The analysis of variance model was used to test whether interactions with genotype were significant. Results: Overall expression of MTHFR was not significantly different in tumour tissue compared to normal colonic mucosa (p=0.24). However, when genotype was taken into account, a statistically significant reduction in MTHFR expression was observed in tumour versus normal tissue from T-carriers (p=0.04) but no difference was observed in CC homozygotes. 73% of the eighteen T-carriers showed reduced expression of MTHFR in tumour tissue compared to 33% of the twenty-one CC homozygotes. Conclusions: Lowered MTHFR expression may contribute to colorectal tumorigenesis among carriers of the T allele at position 677 of MTHFR. This finding suggests that the T carrier subpopulation may benefit more from folate supplementation. The study also illustrates the importance of considering genotypic covariates in the analysis of changes in gene expression involved in carcinogenesis.